Since the fact was made known that, in the area of calcium antagonists of the 1,4-dihydropyridine type, in the case of chiral compounds one enantiomer usually has a distinctly more strongly pronounced cardiovascular action that the other, the need for a suitable, stereoselective synthesis or for a resolution into the enantiomers which also works on the industrial scale has continuously grown. This is seen in the multiplicity of publications and published patent applications, in which resolutions or enantioselective syntheses of chiral 1,4-dihydropyridinecarboxylic acid derivatives are described.
In D. Enders et al. [Tetrahedron Letters 29, 6437 (1988)], an enantioselective synthesis of 1,4-dihydropyridine is described in which the intermediate condensation with a chiral hydrazine leads to a product which is greatly enriched (84 to 98% purity) in one enantiomer. B. Lamm and R. Simonsson [Tetrahedron Letters 30, 6423 (1989)] describe the resolution of felodipine into the enantiomers with the aid of an optically active alcohol. In attempts to obtain manidipine [Drugs of the future 15, 311 (1990)] or alternatively other pharmacologically interesting 1,4-dihydropyridines [such as, e.g., YM-09730, J. Med. Chem. 29, 2504 (1986)] in optically pure form, the synthesis has usually still been carried out recently by the method described in Shibanuma et al. [Chem. Pharm. Bull. 28, 2809 (1980)], in which the monocarboxylic acid regarded as the key compound is prepared from the diester by hydrolysis using sodium 1-dimethylamino-2-propanolate and 2% water. Novel routes to corresponding monocarboxylic acids are described in International Patent Applications WO88/07524 and WO88/09931.